MOLECULAR EPIDEMIOLOGY OF HIV-ASSOCIATED CANCERS
Release Date: April 6, 2000
PA NUMBER: PA-00-086
National Cancer Institute
National Institute of Dental and Craniofacial Research
THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.
This Program Announcement (PA) replaces PA-97-057, which was published in NIH
Guide Volume 26, Number 13, April 25, 1997.
PURPOSE
The Division of Cancer Control and Population Sciences of the National Cancer
Institute (NCI) and the National Institute of Dental and Craniofacial
Research (NIDCR) invite grant applications for interdisciplinary studies to
better understand the molecular epidemiology and role of cofactors in the
etiology of pre-neoplastic conditions and cancers occurring among persons
infected with the human immunodeficiency virus (HIV), specifically those
cancers associated with the DNA viruses, including human papilloma virus
(HPV), Epstein Barr virus (EBV), and human herpes virus 8/Kaposi’s sarcoma
associated herpes virus (HHV8/KSHV). Cofactors of keen interest to the NCI
include host genetic susceptibility and phenotype, age at first acquisition
of the oncogenic virus, temporal association of acquisition of the oncogenic
virus relative to time of HIV acquisition, effect of circulating viral load
of the oncogenic virus, measurements of immune response, and role of
behavioral factors such as tobacco use and diet. It is expected that
enhanced understanding of the molecular epidemiology of these tumors within
the context of HIV-induced host immunodeficiency will yield information
important to cancer control and prevention, including development of
prophylactic vaccines, chemotherapeutic treatment modalities, other
biomedical, and behavioral preventive interventions. The NIDCR is
principally interested in applying molecular epidemiology and the role of co-
factors in the etiology of perineoplastic lesions these DNA viruses cause in
the oral cavity of the immune compromised host. These lesions usually occur
in the oral cavity, early in acute HIV infection and are reestablished when
immune incompetency is a fact.
This PA will expire in two years from the first receipt date. NIH Grants
policies apply to these awards.
HEALTHY PEOPLE 2010
The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2010," a
PHS-led national activity for setting priority areas. This PA, Molecular
Epidemiology of HIV-Associated Cancers, is related to the priority areas of
cancer and HIV infection. Potential applicants may obtain a copy of "Healthy
People 2010" at http://www.health.gov/healthypeople/.
ELIGIBILITY REQUIREMENTS
Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State or local governments, and eligible
agencies of the Federal government. The total requested project period for an
application submitted in response to the PA may not exceed five years.
Foreign applications will receive no support for indirect costs. Domestic
applications may include international components but these components will
receive no support for indirect costs. Racial/ethnic minority individuals,
women, and persons with disabilities are encouraged to apply as Principal
Investigators.
MECHANISM OF SUPPORT
This PA will use the National Institutes of Health (NIH) research project
grant (R01) and competing supplements to existing NCI and NIDCR funded (R01)
grants. Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant. In the case of
competing supplements to existing grants, applicants will be required to
obtain and attach to their applications a document indicating that the
submission of their application has been approved by the Principal
Investigator of the research project grant. This will be especially
important if the application will require access to biological specimens from
a central repository or to existing databases.
Competing supplements must not extend beyond the funding period of the parent
grant, the parent grant must have at least one year remaining in its project
period after award of the supplement.
Specific application instructions have been modified to reflect "MODULAR
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH.
Complete and detailed instructions and information on Modular Grant
applications can be found at
http://grants.nih.gov/grants/funding/modular/modular.htm
RESEARCH OBJECTIVES
Background
Infection by the human retrovirus, HIV, is a major public health problem
throughout the world, particularly in the developing world. Retroviruses may
be directly oncogenic, or may foster the development of human cancers
indirectly through immune suppression and subsequent reactivation of
previously latent human oncogenic viruses. The young age at which most
people in the world become infected with HIV coupled with time spent living
in an immunodeficient state portends that retroviral-associated cancers will
impose a greater impact of years of potential life lost and quality of life
than other cancers.
The NCI and NIDCR have had a continuing interest in the study of the
molecular epidemiology of pre-neoplastic conditions and cancers occurring
among HIV-infected persons. Some cancers, notably those associated with
oncogenic human DNA viruses of the lymphoreticular system (non-Hodgkin’s
lymphoma, Hodgkin’s Disease), soft tissue (Kaposi’s sarcoma,) and epithelial
tissues (anogenital dysplasias and cancers) are significantly increased in
incidence, display an aggressive pattern of development and progression in
HIV-infected individuals, and/or remain refractory to standard therapies. It
is expected that enhanced understanding of the molecular epidemiology of
these tumors within the context of HIV-induced host immunodeficiency will
yield information important to cancer control and prevention, including
development of prophylactic vaccines, chemotherapeutic treatment modalities,
and other biomedical preventive interventions.
The cancers of interest in this PA are ones associated with concomitant
infection with DNA viruses that frequently confer latency, such as Epstein
Barr virus (EBV), human herpes virus 8/Kaposi’s sarcoma associated herpes
virus (HHV8/KSHV) and human papilloma virus (HPV). In each case, infection
by the concomitant virus appears to be necessary for subsequent oncogenesis,
but not sufficient to lead to cancer in every case. Therefore, both
endogenous and exogenous cofactors must play a significant role. For this
PA, cofactors of special interest include host genetic susceptibility and
phenotype, age at first acquisition of the oncogenic virus, temporal
association of acquisition of the oncogenic virus relative to time of HIV
acquisition, effect of circulating viral load of the oncogenic virus,
measurements of immune response, and role of behavioral factors such as
tobacco use and diet.
This PA seeks to encourage research on the molecular and social epidemiology
of preneoplastic conditions among HIV infected persons throughout the world
and comparative epidemiologic studies based in several geographic areas. An
interdisciplinary approach that links the expertise of basic scientists with
that of epidemiologists, clinicians, and behavioral scientists in an
etiologic study is strongly encouraged. Investigations may be conducted in
adults and/or children. The areas of research listed below are not intended
to be all inclusive, but are designed to give the applicant some direction as
to the types of research that the NCI is interested in stimulating. The
NIDCR is interested in the areas of research listed with special focus on
oral viral sentinel lesions and how these may affect HIV progression to AIDS.
o The (treated) natural history of cancers and pre-neoplastic changes in
situations where the temporality of observed events, including timing of
first infection or reactivation of existing infection, may be addressed
o The interplay of route of acquisition of the DNA virus, particularly
HHV8/KSHV, and other cofactors on the molecular epidemiology and natural
history of oncogenesis
o The role of host genetic susceptibility on the molecular epidemiology of
these tumors
o The effect of the age of first acquisition of the oncogenic virus,
particularly with regards to the temporal association with acquisition of HIV
o The relationships of levels of circulating viral load of the oncogenic
virus and of HIV, and the effects on the natural history of both HIV disease
and oncogenesis
o The temporal relationships of immune markers measured both qualitatively
and quantitatively with other variables of interest in the epidemiology of
these tumors
o The effect of past and current use of recreational drugs, including
alcohol, on the epidemiology of these tumors
o The role of diet, nutrition, and dietary supplements, both before
acquisition of the viruses and after the recognition of infection, on the
epidemiology of these tumors
o The effect of past and current use of tobacco products on the epidemiology
of these tumors, including the relationships among nicotine biomarkers,
measures of immune function, and circulating viral load
o The role of psychosocial processes in infection and disease detection and
progression
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS
It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided that inclusion is
inappropriate with respect to the health of the subjects or the purpose of
the research. This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).
All investigators proposing research involving human subjects should follow
the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in
Clinical Research", which have been published in the Federal Register of
March 28, 1994 (FR 59 14508-14513), and in the NIH Guide for Grants and
Contracts of March 18, 1994, Volume 23, Number 11, available on the web at
the following URL address:
http://grants.nih.gov/grants/guide/notice-files/not94-100.html
INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS.
It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research, conducted or supported by
the NIH, unless there are clear and compelling reasons not to include them.
This policy applies to all initial (Type 1) applications submitted for
receipt dates after October 1, 1998.
All investigators proposing research involving human subjects should read the
NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjects that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html
APPLICATION PROCEDURES
The modular grant concept establishes specific modules in which direct costs
may be requested as well as a maximum level for requested budgets. Only
limited budgetary information is required under this approach. The just-in-
time concept allows applicants to submit certain information only when there
is a possibility for an award. It is anticipated that these changes will
reduce the administrative burden for the applicants, reviewers and Institute
staff.
The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants, with the modifications noted below. Applications
kits are available at most institutional offices of sponsored research and
may be obtained from the Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone 301/710-0267, email: grantsinfo@nih.gov.
For those applicants with internet access, the 398 kit may be found at:
http://grants.nih.gov/grants/forms.htm
Applicants are strongly encouraged to call the program contacts listed in
INQUIRIES below with any questions.
BUDGET INSTRUCTIONS
Modular Grant applications will request direct costs in $25,000 modules, up
to a total direct cost request of $250,000 per year. (Applications that
request more than $250,000 direct costs in any year must follow the
traditional PHS 398 application instructions.) The total direct costs must be
requested in accordance with the program guidelines and the modifications
made to the standard PHS 398 application instructions described below:
o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs
(in $25,000 increments) and Total Costs [Modular Total Direct plus Facilities
and Administrative (F&A) costs] for the initial budget period. Items 8a and
8b should be completed indicating the Direct and Total Costs for the entire
proposed period of support.
o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page
4 of the PHS 398. It is not required and will not be accepted with the
application.
o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398. It is not required
and will not be accepted with the application.
o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative
page (see http://grants.nih.gov/grants/funding/modular/modular.htm for sample
pages). At the top of the page, enter the total direct costs requested for
each year. This is not a form page.
o Under Personnel, list key project personnel, including their names,
percent of effort, and roles on the project. No individual salary information
should be provided. However, the applicant should use the NIH appropriation
language salary cap and the NIH policy for graduate student compensation in
developing the budget request.
For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the
nearest $1,000. List the individuals/organizations with whom consortium or
contractual arrangements have been made, the percent effort of key personnel,
and the role on the project. Indicate whether the collaborating institution
is domestic or foreign. The total cost for a consortium/contractual
arrangement is included in the overall requested modular direct cost amount.
Include the Letter of Intent to establish a consortium.
Provide an additional narrative budget justification for any variation in the
number of modules requested.
o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by
reviewers in the assessment of each individual"s qualifications for a
specific role in the proposed project, as well as to evaluate the overall
qualifications of the research team. A biographical sketch is required for
all key personnel, following the instructions below. No more than three
pages may be used for each person. A sample biographical sketch may be
viewed at:
http://grants.nih.gov/grants/funding/modular/modular.htm
- Complete the educational block at the top of the form page,
- List position(s) and any honors,
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years,
- List selected peer-reviewed publications, with full citations.
o CHECKLIST - This page should be completed and submitted with the
application. If the F&A rate agreement has been established, indicate the
type of agreement and the date. All appropriate exclusions must be applied in
the calculation of the F&A costs for the initial budget period and all future
budget years.
The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information
is necessary following the initial review.
The number and title of the PA must be typed on line 2 of the face page of
the application and the YES box must be marked.
Submit a signed, typewritten original of the application, including the
checklist, and five signed, exact, single-sided photocopies, in one package
to:
Center for Scientific Review
National Institutes of Health
6701 Rockledge Drive, Room 1040 - MSC 7710
Bethesda, MD 20892-7710
Bethesda, MD 20817 (for express/courier service)
REVIEW CONSIDERATIONS
Applications will be assigned on the basis of established PHS referral
guidelines. Applications will be evaluated for scientific and technical
merit by an appropriate scientific review group convened in accordance with
the standard NIH peer review procedures.
As part of the initial merit review, all applications will receive a written
critique and undergo a process in which only those applications deemed to
have the highest scientific merit, generally the top half of the applications
under review, will be discussed assigned a priority score, and receive a
second level review by the appropriate national advisory board.
Review Criteria
The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health. The
reviewers will comment on the following aspects of the application in their
written critiques in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals. Each of these
criteria will be addressed and considered by the reviewers in assigning the
overall score weighting them as appropriate for each application. Note that
the application does not need to be strong in all categories to be judged
likely to have a major scientific impact and thus deserve a high priority
score. For example, an investigator may propose to carry out important work
that by its nature is not innovative but is essential to move a field
forward.
Significance: Does this study address an important problem? If the aims of
the application are achieved, how will scientific knowledge be advanced?
What will be the effect of these studies on the concepts or methods that
drive this field?
Approach: Are the conceptual framework, design, methods, and analyzes
adequately developed, well-integrated, and appropriate to the aims of the
project? Does the applicant acknowledge potential problem areas and consider
alternative tactics?
Innovation: Does the project employ novel concepts, approaches or method?
Are the aims original and innovative? Does the project challenge existing
paradigms or develop new methodologies or technologies?
Investigator: is the investigator appropriately trained and well suited to
carry out this work? Is the work proposed appropriate to the experience
level of the principal investigator and other researchers (if any)?
Environment: Does the scientific environment in which the work will be done
contribute to the probability of success? Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements? Is there evidence of institutional support ?
The initial review group will also examine: the adequacy of plans to include
both genders and minorities and their subgroups, and children as appropriate
for the scientific goals of the research and plans for the recruitment and
retention of subjects, the provisions for the protection of human and animal
subjects, and the safety of the research environment.
AWARD CRITERIA
Applications will compete for available funds with all other recommended
applications. The following will be considered in making funding decisions:
quality of the proposed project as determined by peer review, availability of
funds, and programmatic priority.
INQUIRIES
Inquiries concerning this PA are encouraged, particularly during the planning
phase of the grant applications. The opportunity to clarify any issues or
questions from potential applicants is welcome.
Direct inquiries regarding overall programmatic issues to:
Dr. Sandra L. Melnick or Vaurice Starks
Division of Cancer Control and Population Sciences
National Cancer Institute
Executive Plaza North, Room 240, MSC 7395
Bethesda, MD 20892-7395
Telephone: (301) 402-9375
FAX: (301) 402-4279
Email: vs38j@nih.gov
Direct inquiries regarding applications with a primary focus on behavioral
science to:
Dr. Wendy Nelson
Division of Cancer Control and Population Sciences
National Cancer Institute
Executive Plaza North, Room 4064, MSC 7326
Bethesda, MD 20892-7326
Telephone: (301) 435-4590
FAX: (301) 435-7547
Email: wn14x@nih.gov
Direct inquiries regarding application with a primary focus on oral health
to:
Denise Anne Russo, Ph.D.
Infectious Diseases and Immunity Branch
Division of Extramural Research,
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-18B
Bethesda, MD 20892-6402
Telephone: (301) 594-2617
FAX: (301) 480-8318
Email: Denise.Russo@nih.gov
Direct inquiries regarding fiscal matters to:
Bill Wells
Grants Administration Branch
National Cancer Institute
Executive Plaza South, Room 243
6120 Executive Blvd.
Bethesda, MD, 20892
Tel: 301-496-8796
Fax: 301-496-8601
Email: ww14j@nih.gov
Mr. Kevin Crist
Grants Management Branch
Division of Extramural Research
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-38B, MSC 6402
Bethesda, MD 20892-6402
Telephone: (301) 594-4800
FAX: (301) 480-8301
Email: Kevin.Crist@nih.gov
AUTHORITY AND REGULATIONS
This program is described in the Catalog of Federal Domestic Assistance Nos.
93.393, 93.856, and 93.121. Awards are made under authorization Sections 301
and 405 of the Public Health Service Act amended (42 USC 241 and 284) and
administered under NIH grants policies and Federal Regulations 42 CFR 52 and
45 CFR Parts 74 and 92. This program is not subject to the intergovernmental
review requirements of Executive Order 12372 or a Health Systems Agency
Review.
The PHS strongly encourages all grant and contract recipients to provide a
smoke-free workplace and promote the non-use of all tobacco products. In
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking
in certain facilities (or in some cases, any portion of a facility) in which
regular or routine education, library, day care, health care or early
childhood development services are provided to children. This is consistent
with the PHS mission to protect and advance the physical and mental health of
the American people.
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